A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

Leukemia, Myeloid, Acute Clinical Trial

Official title:

A Phase IB Multi-Arm Study With Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02670044
• Other study ID #: GH29914
• Secondary ID: 2015-003386-28
• Status: Completed
• Phase: Phase 1
• Start date: March 9, 2016
• Est. completion date: December 10, 2020

Study information

• Verified date: December 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective for this study is to assess the safety and tolerability as well as preliminary efficacy of venetoclax in combination with cobimetinib, and venetoclax in combination with idasanutlin in patients with relapsed or refractory acute myeloid leukemia (R/R) AML who are not eligible for cytotoxic therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: December 10, 2020
• Est. primary completion date: December 10, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological confirmation of relapsed or refractory AML after prior anti-leukemic therapy by WHO classification
• Ineligible for cytotoxic therapy defined by the following:

a. Age (>/=) 75 years or b. age 18- 74 years with at least one of the following comorbidities: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3 ii. Cardiac history of congestive heart failure requiring treatment or ejection fraction (</=) 50% or chronic stable angina iii. Diffusing capacity of the lungs for carbon monoxide (</=) 65% or forced expiratory volume in the first second of expiration (</=) 65% iv. Creatinine clearance (>/=) 30 mL/min to< 45 mL/min v. any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor before screening and study enrollment.

• Life expectancy of at least 12 weeks
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Adequate liver and renal function

Exclusion Criteria:

• Patients with acute promyelocytic leukemia (French-American-British [FAB] class M3 AML)
• Known active central nervous system (CNS) involvement with AML at study entry
• ECOG Performance Status (>/=) 3 in patients who are (>/=) 75 years old or ECOG Performance Status of 4, regardless of age
• Prior exposure to Bcl-2 inhibitors, murine double minute 2 (MDM2) antagonists or prior exposure to experimental treatment targeting Raf, mitogen-activated protein kinase (MEK), or the mitogen-activated protein kinase (MAPK) RAS/RAF/MEK/ERK MAPK pathway
• Positive for hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) and known history of HIV, malignancy, active infection and cardiovascular diseases (CVs)
• Received strong cytochrome (CYP) 3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers and moderate CYP3A inducers within 7 days prior to initiation of study treatment
• History of symptomatic Clostridium difficile infection within 1 month prior to dosing Additional arm specific exclusion criteria:

Dose Escalation Arm A (Venetoclax and Cobimetinib):

• History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower

Arm B (Venetoclax and Idasanutlin):

• Received the following within 7 days prior to the initiation of study treatment:

Strong CYP2C8 inhibitors or CYP2C8 substrates, OATP1B1/3 substrates

• Received the following within 14 days prior to the initiation of study treatment:

Strong CYP2C8 inducers

• History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests
• Received treatment with oral or parenteral anticoagulants/anti-platelet agents within 7 days prior to initiation of study treatment.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Cobimetinib
Cobimetinib will be administered orally as per schedule in Arm description.
• Idasanutlin
Idasanutlin will be administered orally as per schedule in Arm description.
• Venetoclax
Venetoclax will be administered orally as per schedule in Arm description.

Locations

Country	Name	City	State
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Princess Margaret Cancer Center	Toronto	Ontario
France	Hopital Avicenne, Paris	Bobigny
France	Institut Paoli Calmettes	Marseille
France	CHU de Bordeaux	Pessac
Italy	University of Bologna	Bologna	Emilia-Romagna
Italy	Presidio san salvatore muraglia	Pesaro	Emilia-Romagna
Italy	Universita di Roma	Roma	Emilia-Romagna
United States	University of Colorado	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	MD Anderson Cancer Center	Houston	Texas
United States	USC Norris Cancer Center	Los Angeles	California
United States	Weill Cornell Medical College	New York	New York
United States	UC Davis; Comprehensive Cancer Center	Sacramento	California
United States	Univ of Calif, San Francisco	San Francisco	California
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Dose Limiting Toxicities (DLTs)		From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days
Primary	Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)		Baseline up until 30 days after the last dose of study drug (up to a maximum of 4 years, 9 months)
Secondary	Overall Response Rate (ORR) (Complete Remission (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) + Partial Remission/Partial Response [PR])		Up to 2 years
Secondary	Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp)		Up to 2 years
Secondary	CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate		Up to 2 years
Secondary	Duration of Response (DOR)		Up to 2 years
Secondary	Time to Progression (TTP)		Up to 2 years
Secondary	Progression-Free Survival (PFS)		Up to 2 years
Secondary	Event-Free Survival (EFS)		Up to 2 years
Secondary	Leukemia-Free Survival (LFS)		Up to 2 years
Secondary	Overall Survival (OS)		Up to 2 years
Secondary	Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)		Up to 6 months
Secondary	Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax)		Up to 6 months
Secondary	Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)		Up to 6 months
Secondary	Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax)		Up to 6 months
Secondary	Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)		Up to 6 months
Secondary	Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax)		Up to 6 months
Secondary	Number of Participants Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire		Up to 2 years
Secondary	Rate of Transfusion Independence		Up to 2 years
Secondary	Duration Of Transfusion Independence, Defined As The Number Of Consecutive Days Of Transfusion Independence, Measured From 1 Day After Last Transfusion To Disease Progression Or Subsequent Transfusion		Up to 2 years
Secondary	Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response		Up to 2 years